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lüll Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis Noskova L; Stranecky V; Hartmannova H; Pristoupilova A; Baresova V; Ivanek R; Hulkova H; Jahnova H; van der Zee J; Staropoli JF; Sims KB; Tyynela J; Van Broeckhoven C; Nijssen PC; Mole SE; Elleder M; Kmoch SAm J Hum Genet 2011[Aug]; 89 (2): 241-52Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPalpha). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPalpha in neuronal cells. The resulting depletion of functional CSPalpha might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPalpha in humans and demonstrates the need for detailed investigation of CSPalpha in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation.|Adult[MESH]|Age of Onset[MESH]|Base Sequence[MESH]|Brain/metabolism/pathology/ultrastructure[MESH]|Chromosome Segregation/genetics[MESH]|Exons/genetics[MESH]|Family[MESH]|Female[MESH]|Gene Dosage/genetics[MESH]|Gene Expression Regulation[MESH]|Genes, Dominant/*genetics[MESH]|Genetic Linkage[MESH]|HSP40 Heat-Shock Proteins/*genetics[MESH]|Humans[MESH]|Lipoylation[MESH]|Lysosomes/metabolism/ultrastructure[MESH]|Male[MESH]|Membrane Proteins/*genetics[MESH]|Molecular Sequence Data[MESH]|Mutation/*genetics[MESH]|Neuronal Ceroid-Lipofuscinoses/*epidemiology/*genetics/pathology[MESH]|Neurons/metabolism/pathology/ultrastructure[MESH]|Pedigree[MESH]|Protein Transport[MESH]|Sequence Analysis, DNA[MESH] |